Evaluation of the analgesic efficacy of AZD1940, a novel cannabinoid agonist, on post-operative pain after lower third molar surgical removal

Abstract

Aim To evaluate the analgesic efficacy of AZD1940, a novel peripherally acting cannabinoid CB1/CB2 receptor agonist, in patients undergoing third molar surgical removal. Methods This was a randomized, double-blind, placebo-controlled study in patients scheduled for surgical removal of an impacted lower third molar. Patients received a single oral dose of 800 μg AZD1940, 500 mg naproxen or placebo 1.5 h before surgery. The dose of 800 μg AZD1940 was selected based on earlier data from a single dose study in man, in which it was identified as the highest well tolerated dose. Ongoing post-operative pain (primary variable) and pain on jaw movement were assessed on a visual analog scale (VAS, 0-100 mm) from 0 to 8h postoperatively, deriving the area under the curve of ongoing pain (VAS AUC0-8h), and of pain on jaw movement (VASJM AUC0-8h). The time to requesting rescue medication (acetaminophen) was recorded. Subjective cannabinoid effects were assessed by the visual analog mood scale (VAMS). Results In total, 151 patients were randomized to AZD1940 (n = 61), placebo (n = 59) or naproxen (n = 31). There was no statistically significant difference in pain VAS AUC0-8h or in VASJM AUC0-8h between AZD1940 and placebo. Naproxen significantly reduced both pain VAS AUC0-8h and VASJM AUC0-8h as compared with placebo (p < 0.0001 for both). Significantly fewer patients on naproxen requested rescue medication and the duration of time to rescue was greater, as compared with placebo, whereas there were no significant differences between AZD1940 and placebo in these outcome variables. Statistically significant increases in VAMS items "sedated" and "high" were observed after AZD1940 compared with placebo. The increases in VAMS were numerically small compared with previous findings with a centrally acting cannabinoid. The most commonly observed adverse events (AE) on treatment with AZD1940 were postural dizziness (80% of subjects), nausea (26%), hypotension (21%) and headache (13%), most AE being mild to moderate. Conclusion The CB1/CB2 receptor agonist AZD1940 did not reduce post-operative pain after lower third molar surgical removal at doses exerting subjective cannabinoid effects. Implications Activation of peripheral CB1/CB2 receptors per se is probably of less clinical relevance for the treatment of acute nociceptive pain in man.

Evaluation of the analgesic efficacy and psychoactive effects of AZD1940, a novel peripherally acting cannabinoid agonist, in human capsaicin‐induced pain and hyperalgesia

“…Thus, there were no obvious methodological explanations to the negative efficacy outcome of the present study. Recent negative data on AZD1940 in postoperative dental pain, which can be considered as a model of acute inflammatory pain, are also in agreement with the findings of the present study . According to meta‐analyses of studies on different cannabinoid compounds (e.g.…”

“…Recent negative data on AZD1940 in postoperative dental pain, which can be considered as a model of acute inflammatory pain, are also in agreement with the findings of the present study. 37 According to meta-analyses of studies on different cannabinoid compounds (e. g. cannabis extracts, nabilone, △-9-tetrahydrocannabinol), 1,2 the evidence for cannabinoid efficacy in acute pain is rather weak, with several examples of absent or weak analgesic effects in acute pain treatment or experimental pain in humans. 9,[11][12][13][14][15][16][17] Evidently, AZD1940, a synthetic peripherally acting CB 1 /CB 2 receptor agonist, does not provide any better efficacy than centrally acting cannabinoids.…”

A systematic review of the analgesic efficacy of cannabinoid medications in the management of acute pain

“…In five studies, 5,12,13,15,16 the analgesic efficacy of cannabinoids was found to be equivalent to that provided by placebo. In one study, the use of a cannabinoid (nabilone) was associated with significantly worse pain scores compared to other groups.…”

“…In three studies, the majority of the domains were assessed as being at a low risk of bias, [12][13][14] and in the remaining four studies, 5,[15][16][17] most or all domains were assessed as being at an unclear risk of bias. In total, 27 of the 42 domain assessments were assessed as unclear using the Cochrane Collaboration's tool for assessing risk of bias.…”

“…There did appear to be a tendency for some adverse effects to occur more frequently in the cannabinoid groups than in placebo. In five of the seven studies, [12][13][14][15]17 cannabinoids demonstrated greater adverse effects compared to placebo for some types of adverse events or in particular time periods. However, analysing the adverse effect profile of cannabinoids was difficult due to differences between studies in reporting and defining adverse effects, and that some of the studies did not assess or report the statistical significance of differences between groups.…”